Metabolomic profiling identifies a novel mechanism for heat stroke-related acute kidney injury

Abstract

Heat stroke can induce a systemic inflammatory response, which may lead to multi-organ dysfunction including acute kidney injury (AKI) and electrolyte disturbances. To investigate the pathogenesis of heat stroke (HS)-related AKI, a mouse model of HS was induced by increasing the animal's core temperature to 41oC. Blood samples obtained from the tail vein were used to measure plasma glucose and creati- nine levels. Micro-positron emission tomography-computed tomography (micro-PET/CT), H&E staining and trans- mission electron microscopy were conducted to examine metabolic and morphological changes in the mouse kidneys. Immunohistochemistry (IHC) and western blot analyses were performed to investigate the expression of apoptosis-inducing factor mitochondria-associated 2 (Aifm2), high-mobility group box 1 (HMGB1) and receptor for advanced glycosylation end products (RAGE). Liquid chromatography-mass spectrometry analysis was conducted to find differential metabolites and signaling pathways. The HS mouse model was built success- fully, with significantly increased creatinine levels detected in the serum of HS mice compared with controls, whereas micro-PET/CT revealed active metabolism in the whole body of HS mice. H&E and TUNEL staining revealed that the kidneys of HS mice exhibited signs of hemorrhage and apoptosis. IHC and western blotting demonstrated significant upregulation of Aifm2, HMGB1 and RAGE in response to HS. Finally, 136 differential metabolites were screened out, and enrichment of the ‘biosynthesis of unsaturated fatty acids’ pathway was detected. HS-associated AKI is the renal manifes- tation of systemic inflammatory response syndrome, and may be triggered by the HMGB1/RAGE pathway. Metabolomics indicated increased adrenic acid, docosahexaenoic acid and eicosapentaenoic acid may serve as metabolic biomarkers for AKI in HS. The findings suggested that a correlation between the HMGB1/RAGE pathway and biosynthesis of unsaturated fatty acids may contribute to the progression of HS-related AKI.